OP0279 CAR-T CELL TREATMENT OF REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS- SAFETY AND PRELIMINARY EFFICACY DATA FROM THE FIRST FOUR PATIENTS
Authors: G. Schett, S. Boeltz, F. Müller, A. Kleyer, S. Völkl, M. Aigner, R. Gary, S. Kretschmann, D. Simon, S. Kharboutli, D. Mougiakakos, G. Krönke, M. Andreas
Journal: Annals of the Rheumatic Diseases (2022)

Background While treatment of Systemic lupus erythematosus (SLE) has substantially improved, a subset of patients experiences severe progressive disease despite T- and B cell targeted therapy. Furthermore, drug-free remission and seroconversion is difficult to achieve in SLE to date Objectives To study the safety, tolerability, and preliminary efficacy of deep B cell depletion using autologous CD19 chimeric antigen receptor (CAR) T cells in patients with severe and treatment-refractory SLE Methods The CAR product was manufactured by CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany). T-cells were enriched from the patients’ peripheral blood apheresis product and 1x10 8 cells were used as starting cell population. The cells were transfected with a lentiviral vector encoding an anti-CD19 CAR is composed of the FMC63 scFv, a CD8- derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain (Miltenyi Biotec) and expanded for 12 days. After conditioning with cyclophosphamide/ fludarabine patients received 1x10 6 CD19-CAR-T cells/kg body weight as a single infusion. All SLE treatments with the exception of low dose prednisolone were stopped before CAR-T cell administration. After CAR-T cell treatment, also prednisolone was stopped. Tolerability was assessed by monitoring for Cytokine-release syndrome (CRS), immune-related effector cell neurotoxicity syndrome (ICANS) and infections. Preliminary efficacy was assessed by reaching a Lupus Low Disease Activity State (LLDAS), seroconversion in dsDNA antibodies and ANA and cessation of all SLE-specific treatments Results As of January 22, 2022, our 4 SLE patients had been treated with CD19 CAR-T cells with a follow up of 10 months (patient 1, female aged 20, SLEDAI-2K: 16), 7 months (patient 2, male aged 22; SLEDAI-2K:8), 2 months (patient 3, female aged 22; SLEDAI 2K: 6), and 1 month (patient 4; female aged 24; SLEDAI-2K: 6), respectively. All patients had active severe SLE with failure of standard treatment including pulsed steroids, hydroxychloroquine, mycophenolate, cyclophosphamide, intravenous immunoglobulins, rituximab and belimumab before CD19 CAR-T cell administration. All patients had active kidney disease. No infections occurred. All four patients experienced fever without proof of infectious disease (CRS °I); only one patient was treated with a single dose of tocilizumab. No ICANS and no CRS of other organs occurred. In vivo, CAR-T cells rapidly expanded to a maximum of 27,6% (day 9, patient 1), 41,2% (day 9, patient 2), 11,5% (day 9, patient 3) and 59,1% (day 9, patient 4) of total circulating T cells followed by a typical decline, with circulating CAR-T cells being continuously detectable during the next months. Expansion of CAR T cells preceded the complete and sustained depletion of circulating B cells. Patient 1 experienced sustained drug-free remission (SLEDAI-2K=0) with complete loss of ANA and dsDNA antibodies despite reappearance of B cells at 6 months. Patient 2 also experienced complete loss of ANA and dsDNA antibodies with B cells not yet returned. Low-level proteinuria remained most likely due to previously accrued damage in glomerular filter function (SLEDAI-2K: 2). Patient 3 and patient 4 had a shorter observation period to date but also achieved clinical remission (both SLEDAI-2K 0). All patients met LLDAS and could successfully stop all SLE-specific medication, including glucocorticoids. No SLE flare occurred so far. Conclusion Taken together, these data show that CD19 CAR T-cell therapy is well tolerated and may induce rapid remission of severe refractory SLE. References [1]Mougiakakos D et al., CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med 2021;385:567-569. Disclosure of Interests None declared